The long term goal of the proposed project is to elucidate through conformational studies the mechanism of antithrombin III-thrombin reaction. Since antithrombin III is the major thrombin neutralizer in plasma and this neutralization is accelerated by heparin, this project will also investigate through conformational studies the mechanism whereby heparin affect blood coagulation. Specifically, the objectives of this project will be to combine circular dichroism, difference spectroscopy, dye binding studies and chemical modifications to elucidate: (a) the conformational aspects of purified antithrombin III-thrombin complex; (b) the role of the functional groups of heparin in relation to its ability to change the conformation of antithrombin III; and (c) the conformational aspects of heparin in solution. It is expected that results from the studies on antithrombin III-thrombin complex should provide better understanding of the general problems of protein-protein interactions, and of proteinase-proteinase inhibitor interactions, in particular. Studies on antithrombin III-heparin reaction should increase our understanding of the mechanism of mucopolysaccharide-protein interactions, as well as provide better insights into the structural requirements essential for the anticoagulant activity of heparin.